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More than 64 million Americans have some form of cardiovascular disease, the most prevalent being high blood pressure, myocardial infarction and angina pectoris also known as cardiac pain (The American Heart Association, 2004). While the clinical manifestations of these diseases are well described, comparatively little is known regarding the neural mechanisms underlying the control of the heart and circulation. We utilize a combination of experimental and computational techniques in developing a functional understanding of how individual cardiac sensory neurons and brainstem neural circuits both encode and process cardiovascular information. Fundamental to the operation of all neurons are ion channels, which are membrane bound proteins that give rise to the electrical characteristics of these cells. Ion channels or subcellular modulators of ion channel function are often targets for pharmacological interventions in treating cardiovascular disease. In the laboratory, we use patch clamp electrophysiology to study the impact of ion channel dynamics upon the discharge characteristics of cardiac sensory neurons. In the computer, we use biologically realistic mathematical models of cardiac sensory neurons and techniques of dynamical systems analysis to provide a conceptual framework with which to meaningfully interpret experimental results as well as a way of better directing and organizing future studies. An additional aspect of our work involves the development of instrumentation that moves our theoretical models out of the computer and into the research laboratory where they can be used as real-time tools for studying ion channel dynamics. Know as Dynamic Current Clamping, this technique makes possible the biological testing of model-based hypothesis as well as the study of higher order models of ion channel structure and function, which previously could not be validated experimentally. Recent results from our lab have demonstrated how tetrodotoxin-resistant Na+ ion channels, a special class of ion channels closely associated with pain sensation, can exert considerable influence over the responsiveness of a particular class of cardiac sensory neurons. We anticipate that these results may lead to more efficient development and effective application of pharmacological interventions for the management of cardiac pain. Laboratory research and experimental methodologies
1. Electrophysiology of vagal afferent neurons - ion channel biophysics using the patch clamp technique 2. Central integration of vagal afferents - synaptic transmission using a brainstem slice preparation 3. Mechanoreception in vagal afferents - neuromechanics using an arterial baroreceptor fiber preparation 4. Computational neuroscience - models of sensory neuron function, allosteric models of channel gating 5. Instrumentation for neuroscience research - dynamic current clamp, real-time digital signal processing Selected Publications: Jin YH, Bailey TW, Li BY, Schild JH, Andresen MC. P2X and VR1 receptor activation releases glutamate from separate cranial afferent terminals in nucleus tractus solitarius. Journal of Neuroscience, Vol. 24(20), 4709-4717, 2004. Jin YH, Bailey TW, Doyle MW, Li BY, Chang SK, Schild JH, Mendelowitz D, and Andresen MC. Ketamine differentially blocks sensory afferent synaptic transmission in medial nucleus tractus solitarius (mNTS). Anesthesiology. Vol. 98(1), 121-32, 2003. Li BY and Schild JH. Patch clamp electrophysiology in the nodose ganglia of the adult rat. J. Neuroscience Methods, Vol. 115(2), 157-67, 2002. Glazebrook PA, Ramirez AN, Schild JH, Shieh CC, Doan T, Wible BA, Kunze DL. Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J. of Physiology, Vol. 541, 467-82, 2002. Schild JH, Kunze DL. An experimental and modeling study of Na+ current heterogeneity in rat nodose neurons and its impact on neuronal discharge. J. Neurophysiology, Vol. 78, 3198-3209, 1997. |
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